Field of the Invention
The present disclosure relates to pharmaceutical composition and method for screening a therapeutic agent for preventing or treating heart failure.
The Sequence Listing submitted in text format (.txt) filed on Sep. 21, 2012, named “Rev Sequence Lising.txt”, (created on Sep. 21, 2012, 7 KB), is incorporated herein by reference.
Description of the Related Art
A heart disease is considered as one of the most prevalent adult diseases along with diabetes and hypertension. The heart disease is responsible for 17 million annual deaths over worldwide, and causes about 2,600 daily deaths in the United States which is one of the most serious countries for heart diseases. Therefore, the development of heart disease-related medications and treatments is actively being made in advanced countries, and the global market size reaches about 45 billion dollars. Under the recognition of importance for heart diseases, lots of studies have been undergone in Korea.
As the heart is subject to the blood pressure overload due to several pathogenic factors such as obesity, diabetes, and hypertension, it shows myocardial hypertrophy. The cell proliferation no longer occurs in the heart because the embryological differentiation of the heart is completely terminated. Therefore, it is the only way to strengthen the cardiac contractility that increases the size of the existing cardiac muscle cells, when strengthening the cardiac output is needed. This physiological phenomenon is called myocardial hypertrophy.
The cardiac muscle known as cardiomyocytes or cardiac myocytes is one of striated muscles found in a heart wall. The cardiac muscle is similar to the skeletal muscle in the senses that both of them have striated pattern and contractility, but fundamentally different from the smooth muscle in terms of structure, function and stimulus-contraction response.
The myocardial hypertrophy is considered as the compensation response for external stimuli but itself is not a serious problem. However, the myocardial hypertrophy may be exacerbated to the heart failure when it keeps last for a long period of time [1-3]. The heart failure is characterized by a defective heart function by a thinner heart wall by apoptosis and an extended lumen of the atrium and ventricle. In human, the myocardial hypertrophy (more accurately, LVH: left ventricular hypertrophy) occurs by various etiological causes and the myocardial infarction occurs by the coronary artery obstruction. They induce the diastolic and systolic dysfunction, respectively, and may be maintained without specific symptoms for several years or decades depending on persons. If the myocardial hypertrophy and the myocardial infarction are developed to the heart failure, the sudden death is very likely to occur in several months or years. Although the myocardial hypertrophy per se is not considered as a serious problem, it is classified as a risk factor which may result in the sudden death because of its higher progression probability to the heart failure.
A group of matricellular proteins known as the CCN (Cyr61, CTGF, and Nov) family has recently been described [5]. These are secreted, cell- and matrix-associated proteins with diverse roles in various aspects of cell function, including wound repair, vascular disease, fibrosis, angiogenesis, tumorigenesis, cell differentiation and survival [6]. Previous studies have indicated that CCN2, also known as CTGF (Connective Tissue Growth Factor), plays a role in the development of cardiac fibrosis. The expression of CCN2 was induced by TGF-β, a pro-fibrotic cytokine, in cardiac fibroblasts and cardiomyocytes [7]. CCN2 was shown to be an essential mediator of the physiological effects of TGF-β [8]. CCN2 has also been implicated in cardiac hypertrophy [9]. The expression of CCN2 has been reported to be elevated in the hypertrophied and failing hearts [9-11]. Treatment with CCN2 in isolated cardiomyocytes caused an Akt signaling-mediated increase in cell size [12]. Transgene-mediated overexpression of CCN2 in the mouse heart promoted the age-dependent development of cardiac hypertrophy, but did not induce cardiac fibrosis [13].
Throughout the specification, a number of publications and patent documents are referred to and cited. The disclosure of the cited publications and patent documents is incorporated herein by reference in its entirety to more clearly describe the state of the related art and the present disclosure.